title: Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor.
abstract: Cyclooxygenase (COX)-2 inhibitors have been reported to potentially modulate the resistance of cancer cells to chemotherapeutic drugs by affecting multidrug resistance 1 (MDR1) expression. In the present study, we investigated the association between COX-2 and MDR1 expression in endometrial cancers and evaluated the effects of the COX-2 inhibitor, etodolac, in combination with paclitaxel on paclitaxel-resistant endometrial cancer cells. The relationship between COX-2 and MDR1 mRNA expression was examined by quantitative PCR in 36 endometrial cancer specimens. The paclitaxel-resistant cell line OMC-2P was established from OMC-2 cells. Paclitaxel (1 µg/ml) with or without etodolac (10 µg/ml) was added to OMC-2 and OMC-2P cells, and COX-2 and MDR1 mRNA expression levels were examined. The concentration of prostaglandin E2 (PGE2) in the supernatant of each cell line was examined by enzyme-linked immunosorbent assay. The function of MDR1 was determined by intracellular accumulation of rhodamine 123 using flow cytometry, and the concentration of intracellular paclitaxel was determined by high-performance liquid chromatography. We found a positive relationship between COX-2 and MDR1 mRNA expression in endometrial cancer. Both COX-2 mRNA expression and PGE2 production were elevated in resistant OMC-2P cells when compared to non-resistant OMC-2 cells. Additionally, MDR1 mRNA expression was markedly upregulated in OMC-2P cells. In OMC-2 cells, COX-2 and MDR1 mRNA levels were significantly upregulated by paclitaxel treatment and downregulated by co-administration with etodolac. In OMC-2P cells, COX-2 mRNA expression was also significantly upregulated by paclitaxel treatment and tended to be downregulated by co-administration with etodolac. Moreover, co-administration of paclitaxel and etodolac suppressed the induction of MDR1 mRNA. Rhodamine 123 efflux was increased in OMC-2P cells when compared to the efflux in the OMC-2 cells and was increased in response to paclitaxel treatment. Co-administration of paclitaxel and etodolac in both cell lines resulted in decreased rhodamine 123 efflux. The actual concentration of intracellular paclitaxel in OMC-2P cells was significantly lower than that in OMC-2 cells treated with paclitaxel alone and was significantly increased after co-administration of paclitaxel and etodolac. These findings suggest that paclitaxel resistance may be associated with COX-2 and MDR1 expression in cancer cells. Co-administration of COX-2 inhibitors and paclitaxel may have a key role in modulating or overcoming paclitaxel resistance in endometrial cancers.
authors.affiliation: Department of Obstetrics and Gynecology, Fujita Health University, Banbuntane Hotokukai Hospital, Nagoya, Aichi 454‑8509, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Kunimi
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Torii
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kawamura
authors.forename: Rina
authors.initials: R
authors.lastname: Kato
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tsukada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Udagawa
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017308:Etodolac / Q000008:administration & dosage*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D052246:Cyclooxygenase 2 Inhibitors; D012333:RNA, Messenger; D017308:Etodolac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017239:Paclitaxel